Role of histotripsy synergized CD40 signaling in the re-engineering of cold tumors

组织解剖协同 CD40 信号传导在冷肿瘤再造中的作用

• 批准号: 10390557
• 负责人: Ashish Ranjan
• 金额: $ 43.32万
• 依托单位: OKLAHOMA STATE UNIVERSITY STILLWATER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10390557
• 关键词: Abscopal effect; Adverse effects; Aftercare; Agonist; Anti-CD40; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Antigens; Biological Assay; CT26; CTLA4 gene; Cancer Patient; Canis familiaris; Cells; Clinical; Clinical Trials; Colonic Neoplasms; Data; Disease; Disease remission; Distant; Dose; Encapsulated; Engineering; Focused Ultrasound; Focused Ultrasound Therapy; Genes; Goals; Growth; Human; Immune; Immune checkpoint inhibitor; Immunization; Immuno-Chemotherapy; Immunologic Tests; Immunologics; Immunosuppression; Immunotherapy; Infiltration; Injections; Location; Malignant - descriptor; Malignant Neoplasms; Mechanics; Mediating; Metastatic Melanoma; Modality; Modeling; Mus; Neoplasm Metastasis; Pancreas; Pathway interactions; Patients; Pharmaceutical Preparations; Polymers; Prostate; Proteins; Radiation therapy; Radio; Reagent; Regimen; Relapse; Resistance; Role; Signal Pathway; Signal Transduction; Skin Cancer; Solid; Solid Neoplasm; Sonication; Survival Rate; T-Lymphocyte; TNFRSF5 gene; Technology; Testing; Therapeutic; Tissues; Translating; Translations; Tumor Antigens; Tumor Burden; Tumor Immunity; Tumor Tissue; Tumor-infiltrating immune cells; base; cell motility; checkpoint therapy; clinically relevant; combinatorial; cytokine; cytotoxic; exhaust; experience; image guided; immune activation; immunogenic; immunogenicity; immunosuppressed; improved; improved outcome; in situ vaccination; innovation; lymphoid organ; melanoma; millisecond; novel; preservation; progenitor; programmed cell death ligand 1; programmed cell death protein 1; response; success; survival outcome; tumor; tumor microenvironment

Project Summary Advanced-stage metastatic melanoma is the deadliest form of skin cancer, typically resistant to chemo- and radiotherapy. For such patients, the advent of immune checkpoint inhibitors (ICIs) has been a revolutionary change, improving tumor remission and survival rates, reversing prior lack of progress. Although promising, a large proportion of patients, especially those with poorly immunogenic ("cold") tumors, show only modest response to ICIs, and even responders relapse frequently. New tumor-reengineering technologies are urgently needed to improve survival rates in patients with immunoresistant cold tumors. The objective of this project is to optimize an innovative combinatorial therapy based on local focused ultrasound-based histotripsy (HT) and anti- CD40 agonist antibody (aCD40) encapsulated polymeric microparticles (CMPs) to reprogram cold melanoma tumors. HT non-invasively and rapidly generates acellular antigen depots with sharp boundaries in solid cancers, while aCD40 activates antigen-presenting cells (APCs). Our murine melanoma studies found that CMP is more efficacious compared to soluble aCD40 alone, and when combined with ICI/HT achieves complete remission of untreated tumors. Based on this premise, we will test the central hypothesis that intratumorally-administered CMPs that serve the dual functions of tumor antigen capture and sustained CD40 activation with HT will achieve durable remission of locally-treated and remote untreated melanomas. To test our hypothesis, the aims are to 1) Determine efficacy of the HT and CMP combined regimen in murine tumor models varying in immunogenicity and burden, 2) Elucidate ICI resistance reversal mechanisms that drives abscopal effects with HT and CMP, and 3) translate our findings to clinical trials in dog veterinary patients with spontaneous malignant melanoma. Dog melanoma resembles human melanoma, and metastasizes aggressively, and is advantageous for assessing translatability of our combinatorial therapy. Transforming immunologically “cold” tumors to immunogenic ones in advanced stages of cancer is a challenging goal. The project results will enable rapid activation of cold melanomas by locally generating large tumor antigen depots that can synergize with CD40 signaling to improve efficacy against locally treated and distant untreated tumors. Our studies in clinically- relevant models will inform feasibility of improving survival in a large proportion of metastatic melanoma patients with immunotherapy-resistant tumors.

项目摘要 晚期转移性黑色素瘤是皮肤癌最致命的形式，通常对化学和化学抗性抗性 放疗。对于此类患者，免疫抑制剂（ICI）的冒险一直是革命性的 变化，改善肿瘤的缓解和存活率，逆转先前缺乏进展。虽然很有希望， 很大一部分患者，尤其是免疫原性（“冷”）肿瘤的患者仅显示适中 对ICI，甚至响应者的反应。新的肿瘤重新工程技术紧急是 需要提高免疫抗原肿瘤患者的存活率。该项目的目的是 优化基于局部集中超声疗法（HT）和抗抗的创新组合疗法 CD40激动剂抗体（ACD40）封装的聚合微粒（CMP）以重编程冷黑色素瘤 肿瘤。 HT非侵入性，迅速产生固体癌症中具有锐角的细胞抗原沉积物， 而ACD40激活抗原呈递细胞（APC）。我们的鼠类黑色素瘤研究发现CMP更多 简单地与仅固体ACD40进行比较，当与ICI/HT结合使用时，可以完全缓解 未处理的肿瘤。基于此前提，我们将测试中心假设，即肿瘤内管理 使用HT的肿瘤抗原捕获和持续CD40激活的双重功能的CMP将实现 局部治疗和远程未经治疗的黑色素瘤的持久缓解。为了检验我们的假设，目的是 1）确定HT和CMP合并方案在鼠肿瘤模型中的效率变化 和伯恩，2）阐明ICI抗性逆转机制，这些机制驱动HT和CMP的潜在效应， 3）将我们的发现转化为狗兽医患者的临床试验。 狗黑色素瘤类似于人类黑色素瘤，并积极转移，对 评估我们组合疗法的翻译性。将免疫学“冷”肿瘤转化为 在癌症晚期阶段的免疫原性是一个挑战目标。项目结果将使快速 通过局部产生可以与CD40协同作用的大肿瘤抗原沉积物来激活冷黑色素瘤 信号传导以提高针对局部治疗和远处未处理肿瘤的效率。我们在临床上的研究 相关模型将为大量转移性黑色素瘤患者的可行性提供改善生存的可行性 具有免疫疗法的肿瘤。